The hypothesis addressed by this project is that selenium, vitamin E, and lycopene protect against prostate cancer development through their antioxidant activities. There are no definitive data about this from human studies. There are very few reports of experimental studies that tested this hypothesis, and those that did used models systems that do not involve oxidative stress mechanisms. Furthermore, there are no reports of studies that have investigated the probably critical synergisms that may exist between these antioxidants. Therefore, the purpose of this project is: (a) To address this hypothesis in an animal model of prostate carcinogenesis that does involve oxidative stress mechanisms; (b) To generate with this model data in support of the notion that antioxidant activity is a major mechanism by which selenium, vitamin E, and lycopene protect against prostate cancer; (d) To explore the efficacy and antioxidant activity of gamma-tocopherol. The project will use a unique animal model that is suitable to test chemopreventive activity of antioxidants and it will make a contribution to critically assessing the rationale for the SELECT trial; and (d) To determine the magnitude of the protective activity of these antioxidants individually and in combination to provide efficacy information in support of the design of prevention clinical trials. The Specific Aims of the project are: (1) To determine the efficacy of selenium, vitamin E (alpha-tocopherol), and lycopene to prevent prostate cancer in NBL rats treated with estradiol & testosterone. This model importantly involves oxidative stress mechanisms. The antioxidants will be given in the diet at non-toxic doses comparable to those used in previous studies with prostate cancer models that do not involve oxidative stress. (2) To determine whether treatments with these antioxidants reduce oxidative stress parameters related to oxidation of DNA bases, lipid peroxidation, and inactivation or alteration of antioxidant enzymes. These parameters will be measured in the areas of the prostate of NBL rats where treatment with estradiol & testosterone induces cancer and preneoplastic lesions, and the effects observed will be related to the outcome of the efficacy studies of Specific Aim 1. Prostatic antioxidant levels will also be measured. (3) To determine the efficacy and antioxidant activity of gamma-tocopherol There are epidemiological indications that gamma-tocopherol has stronger protective effects against prostate cancer than alpha-tocopherol and the effects of gamma-tocopherol will be compared with those of the alpha-tocopherol studies of Aims 1 and 2. (4) To determine the efficacy of combination treatment with the three antioxidants to prevent prostate cancer in NBL rats treated with estradiol & testosterone and to determine whether these treatments reduce oxidative stress parameters. The observed effects will be compared with the outcome of the single agent studies of Aims 1 and 2.